Cross-platform analysis reveals cellular and molecular landscape of glioblastoma invasion.

BACKGROUND: Improved treatment of glioblastoma (GBM) needs to address tumor invasion, a hallmark of the disease that remains poorly understood. In this study, we profiled GBM invasion through integrative analysis of histological and single-cell RNA sequencing (scRNA-seq) data from 10 patients. METHODS: Human histology samples, patient-derived xenograft mouse histology samples, and scRNA-seq data were collected from 10 GBM patients. Tumor invasion was characterized and quantified at the phenotypic level using hematoxylin and eosin and Ki-67 histology stains. Crystallin alpha B (CRYAB) and CD44 were identified as regulators of tumor invasion from scRNA-seq transcriptomic data and validated in vitro, in vivo, and in a mouse GBM resection model. RESULTS: At the cellular level, we found that invasive GBM are less dense and proliferative than their non-invasive counterparts. At the molecular level, we identified unique transcriptomic features that significantly contribute to GBM invasion. Specifically, we found that CRYAB significantly contributes to postoperative recurrence and is highly co-expressed with CD44 in invasive GBM samples. CONCLUSIONS: Collectively, our analysis identifies differentially expressed features between invasive and nodular GBM, and describes a novel relationship between CRYAB and CD44 that contributes to tumor invasiveness, establishing a cellular and molecular landscape of GBM invasion.

Cerebrospinal fluid circulating tumor DNA depicts profiling of brain metastasis in NSCLC.

Brain metastasis (BM) genetically diverges from the primary tumor in non-small-cell lung cancer (NSCLC). Hence, accurately capturing clinically relevant alterations is pivotal for the delivery of targeted therapies. Circulating tumor DNA (ctDNA) sequencing has emerged as a promising liquid biopsy in the biomarker-based clinical management of recurrent and extracranial metastatic NSCLC. However, the absence of simultaneous sequencing data from brain metastatic sites prevents the definitive evaluation of the efficacy of ctDNA in representing genetic profiles in BM. Here, we performed parallel genomic comparisons between matched BM and primary tumor DNA, plasma ctDNA, and cerebrospinal fluid (CSF) ctDNA. The results indicated that CSF ctDNA had a greater ability than plasma ctDNA to comprehensively represent the mutational landscape of BM, with CSF ctDNA detecting all BM mutations in 83.33% of patients, while plasma ctDNA was only 27.78%. Mutant allele frequency (MAF) in CSF ctDNA was highly correlated with the tumor size of BM (r = 0.95), and the mean MAF in CSF ctDNA was higher than that in plasma ctDNA (38.05% vs. 4.57%, respectively). MAF and tumor mutational burden in CSF ctDNA were strongly associated with those in BM (r = 0.96 and 0.97, respectively). Of note, CSF ctDNA had significantly higher concordance with BM than plasma ctDNA (99.33% vs. 67.44%), facilitating the identification of clinically relevant mutations. Moreover, we found that plasma ctDNA has stronger profiling performance, with a concordance of 93.01% in multiple brain metastases, equivalent to CSF ctDNA. Collectively, our study indicates that CSF ctDNA is superior to plasma ctDNA in accurately representing the profiling of single BM. Plasma ctDNA could be an alternative liquid biopsy material to be applied in multiple brain metastatic NSCLC.

Targeted Delivery of Chemo-Sonodynamic Therapy via Brain Targeting, Glutathione-Consumable Polymeric Nanoparticles for Effective Brain Cancer Treatment.

Glioblastoma (GBM) is the most aggressive tumor of the central nervous system and remains universally lethal due to lack of effective treatment options and their inefficient delivery to the brain. Here the development of multifunctional polymeric nanoparticles (NPs) for effective treatment of GBM is reported. The NPs are synthesized using a novel glutathione (GSH)-reactive poly (2,2″-thiodiethylene 3,3″-dithiodipropionate) (PTD) polymer and engineered for brain penetration through neutrophil elastase-triggered shrinkability, iRGD-mediated targeted delivery, and lexiscan-induced autocatalysis. It is found that the resulting lexiscan-loaded, iRGD-conjugated, shrinkable PTD NPs, or LiPTD NPs, efficiently penetrate brain tumors with high specificity after intravenous administration. Furthermore, it is demonstrated that LiPTD NPs are capable of efficient encapsulation and delivery of chemotherapy doxorubicin and sonosensitizer chlorin e6 to achieve combined chemotherapy and sonodynamic therapy (SDT). It is demonstrated that the capability of GSH depletion of LiPTD NPs further augments the tumor cell killing effect triggered by SDT. As a result, treatment with LiPTD NPs effectively inhibits tumor growth and prolongs the survival of tumor-bearing mice. This study may suggest a potential new approach for effective GBM treatment.

Phytonanomaterials as therapeutic agents and drug delivery carriers.

Medicinal plants have been a major resource for drug discovery. Emerging evidence shows that in addition to pharmacologically active components, medicinal plants also contain phytochemical nanomaterials, or phytonanomaterials, which form nanoparticles for drug delivery. In this review, we examine the evidence supporting the existence of phytonanomaterials. Next, we review identification, isolation, and classification of phytonanomaterials, characteristics of phytonanomaterial-derived nanoparticles, and molecular mechanisms of phytonanomaterial assembly. We will then summarize the current progress in exploring phytonanomaterial-derived NPs as therapeutic agents and drug delivery carriers for disease treatment. Last, we will provide perspectives on future discovery and applications of phytonanomaterials.